It is clear that fescue toxicosis results in major impacts on the cardiovascular system. These impacts include vasoconstriction, a thickened medial layer of blood vessels, endothelial cell damage, vascular stasis and thrombosis, ischemia, and finally gangrene (Thompson et al., 1950; Burfening, 1973; Culvenor, 1974; Garner and Cornell, 1978; Seawright, 1982; Coppock et al., 1989; Dyer, 1993; Oliver and Schultze, 1997; Shappell, 2003; Oliver, 1997, 2005; Klotz et al., 2007). The thickened medial layer of blood vessels in animals with fescue toxicosis has been linked to hyperplasia of the smooth muscle layer induced by ergot alkaloids, as reported by Strickland et al. (1996) using isolated vascular smooth muscle cells in vitro. Moreover, results of in vitro vascular bioassays (Solomons et al., 1989; Oliver et al., 1992, 1993, 1998; Klotz et al., 2006, 2007) have strongly suggested that the hyperthermia of fescue toxicosis is associated with the ergot alkaloids of E+ tall fescue. By inducing vasoconstriction as well as vascular smooth muscle cell hyperplasia (Oliver and Schultze, 1997) and endothelial cell damage, these alkaloids could reduce substantially blood flow to peripheral tissues, thereby reducing efficiency of heat transfer from core body tissue to the surface for dissipation. These postulations are substantiated as result of peripheral vasoconstriction being a measurable response to consumption of E+ tall fescue (Rhodes et al., 1991; Oliver et al., 1998). Additionally, Aiken et al. (2007) showed with Doppler ultrasonography that heifers consuming E+ tall fescue seed (0.85 and 0.36 mg/g dry matter for ergovaline and ergovalinine, respectively) had reduced caudal artery area and blood flow rates in comparison with baseline measures (i.e., animal as own control) as well as to measures in heifers receiving E- seed. However, it is currently unclear which ergot alkaloids, metabolites thereof, and/or alkaloid combinations found in E+ tall fescue are the primary toxicants or the combination of mechanisms by which these alkaloids may affect cardiovascular function.

Ergovaline has been reported as the most abundant of the ergopeptine alkaloids produced in E+ tall fescue (Yates et al., 1985; Lyons et al., 1986). This led to the early presumption that ergovaline was the primary toxicant in the fescue toxicosis syndrome. Much of the pharmacologic research concerning ergopeptines has been conducted using ergotamine, an ergopeptine chemically similar to ergovaline, but produced at much lower levels in E+ tall fescue (Yates et al., 1985). Ergotamine has been used primarily because of its broader availability as a result of its being used for treatment of migraines. Ergotamine has been shown to elicit contractile responses in bovine dorsal pedal vein (Solomons et al., 1989), cranial branch of the bovine lateral saphenous vein (Klotz et al., 2007), equine lateral saphenous vein and dorsal metatarsal artery (Abney et al., 1993), and rat tail artery (Schöning et al., 2001). Similarly, ergovaline has been shown to be a potent vasoconstrictor of bovine uterine and umbilical arteries (Dyer, 1993) and rat tail and guinea pig iliac arteries (Schöning et al., 2001), as well as most recently of the cranial branch of the bovine lateral saphenous vein (Klotz et al., 2006, 2007; Fig. 12-1A). Additional recent research by Klotz et al. (2006, 2007; Fig. 12-1C, 12-1D) clearly indicates that the ergopeptines, ergovaline and ergotamine, are more potent and efficacious vasoconstrictors than lysergic acid. In fact, lysergic acid is at least 1000-fold less potent than ergovaline. Ergovaline begins its contractile response at the 10-8 M concentration and equals the contractile response of 10-4 M lysergic acid at a concentration of 10-7 M. Whereas the maximal contractile response of lysergic acid was 15 to 20% of the norepinephrine reference dose (10-4 M), that of ergovaline was 70 to 105% of the norepinephrine reference dose.


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Fig. 12-1. Contractile response of the cranial branch of the bovine lateral saphenous vein in vitro to various alkaloid treatments. Data were compiled from several published (Klotz et al. 2006, 2007) and unpublished research trials (unpublished data, J.R. Strickland lab, 2007). (A) Contractile response of ergovaline in vessels collected from abattoir animals (Klotz et al., 2007) and surgical biopsy of naïve animals (Klotz et al., 2008). (B) Contractile response of ergocryptine in vessels from biopsy of naïve animals (Klotz et al., 2008) and ergotamine response in vessels collected from abattoir animals (Klotz et al., 2007). (C) Contractile response of lysergic acid, ergonovine, and ergocryptine in vessels biopsy of naïve animals (Klotz et al., 2008) and lysergic acid in vessels collected from abattoir animals (Klotz et al., 2007). (D) Contractile response of N-acetylloline in vessels collected from abattoir animals (Klotz et al., 2008).


Prior exposure to ergot alkaloids (e.g., tissue from abattoir animals; Klotz et al., 2007, 2008; Fig. 12-1A, 12-1B) apparently attenuates the effect of these alkaloids on vasoconstriction in vitro when compared with animals with no prior exposure (i.e., naïve cattle). These observations support earlier findings by Oliver et al. (1998), in which a shift in α-2-adrenergic receptor activity was noted as being affected by prior exposure to E+ tall fescue (Fig. 12-2). Additional controlled studies are needed to confirm and define these apparent differences between cattle consuming E+ and E- tall fescue. Klotz et al. (2008) also showed that apparently there was no synergistic, subtractive, or additive effects of ergovaline, lysergic acid, or N-acetylloline in mixtures on vasoactive potential of these alkaloids in this in vitro model. As expected, N-acetylloline showed no contractile effect in this system (Fig. 12-1D), providing evidence that the saturated pyrrolizidine alkaloid class of compounds may not be involved in fescue toxicosis. As the in vitro studies of Klotz et al. (2006, 2007) show, lysergic acid is at best a weak vascular toxicant in the periphery. As such, it is tempting to speculate that the primary toxicants associated with tall fescue will be those ergot alkaloids that are more structurally complicated, such as ergovaline.

Although the exact mechanism of alkaloid-induced vascular toxicity in ungulates is not completely clear, several lines of evidence implicate adrenergic and serotonergic receptor systems (Oliver, 1997, 2005). For example, pharmacologic treatments for reversal of severe vaso-spastic disease induced by ergot alkaloids typically have been most successful when α-adrenergic receptor antagonists have been used (Byrne-Quinn, 1964; Fedotin and Hartman, 1970; McLoughlin and Sanders, 1972; Greene et al., 1977; Larson et al., 1993). This would implicate the α-adrenergic receptors as good candidate targets for alkaloid interaction at the level of the blood vessel. In fact, Oliver et al. (1998) demonstrated clearly that segments of the cranial branch of the lateral saphenous vein from cattle consuming E+ tall fescue have increased contractile response to BHT-920, a selective α-2-adrenergic receptor agonist (Fig. 12-2), when compared with those from animals grazing E- tall fescue pasture. Oliver et al. (1993) also reported that the serotonin 5-HT2 and α-1-adrenergic receptors were sites of interaction for the ergot alkaloid, lysergic acid, a relatively weak vascular contractor.


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Fig. 12-2. Mean contractile dose response of lateral saphenous vein (cranial branch) of cattle in vitro to the selective α-2-adrenergic receptor agonist BHT-920. Cattle were pastured on E- (0%) or E+ (100%) (N. coenophialum) tall fescue for 55 to 85 d (mid March to mid June, 1993, 1994, and 1996). Treatments (E- and E+) were different (P < 0.05). From Oliver et al. (1998).

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